1. Field of the Invention
The present invention relates generally to a method for identifying agents effective in modulating prokineticin receptor, and more specifically to the treatment of cerebrovascular diseases and seizure disorders.
2. Background Information
Prokineticin receptors are G-protein coupled receptors that bind secreted proteins, namely, prokineticin 1 (PK1) and prokineticin 2 (PK2) inducing cellular responses. Prokineticins have roles in several biological functions, including circadian rhythm; angiogenesis; gastric contractility and motility; gastric acid and pepsinogen secretion; pain; and neurogenesis. The role of the prokineticin receptor pathway implicates improper prokineticin signaling in a variety of disease and disorders. As such, modulation of the prokineticin signaling pathway is implicated in treatment of a variety of disorders and diseases, such as such as cerebrovascular injury and seizure disorders. Accordingly, it is desirable to identify drugs that modulate receptor activity to treat associated disorders.
Cerebrovascular disease includes any abnormality of the brain resulting from a pathologic process of a blood vessel, including an occlusion of a blood vessel lumen by thrombus or embolus, a rupture of a blood vessel, an altered permeability of a blood-vessel wall, and increased viscosity or other change in the quality of blood. Cerebrovascular disease typically manifests as a stroke and characterized as the death of brain tissue that results from lack of blood flow and insufficient oxygen to the brain.
A stroke can be ischemic or hemorrhagic. In an ischemic stroke, the blood supply to part of the brain is reduced or terminated either by a blood clot that blocks a blood vessel or by atherosclerosis. Reducing or terminating blood flow to the brain is known as cerebral ischemia. Still cerebral ischemia can also arise from the failure of circulation and hypotension from severe and prolonged cardiac decompensation or shock. In a hemorrhagic stroke, the brain is damaged by a blood vessel bursting, which prevents normal blood flow and allows blood to leak into an area of the brain. When blood leaks into the brain, a hematoma is formed in the brain and blood can spread into ventricles and subarachnoid space. When cerebral ischemia is of sufficient severity and duration, cell injury can progress to cell death. When blood flow resumes to an organ after temporary cessation, this is known as ischemic reperfusion of the organ. Conditions observed with ischemia reperfusion injury include neutrophil infiltration, necrosis, and apoptosis.
Strokes are the leading cause of death in the United States after heart disease. Therefore, it is desirable to develop treatments for cerebrovascular diseases, including cerebral ischemia, cerebral hemorrhage, ischemic stroke, hemorrhagic stroke, and ischemic reperfusion injury.
Epilepsy is a prevalent neurological disorder, and an umbrella term that is used to describe multiple disorders of recurrent and unprovoked seizures. Genetic studies of human epilepsies and mouse mutants have indicated that voltage-gated ion channels are crucial elements in neuronal excitation and are therefore important in seizure initiation and propagation. Ligand-gated ion channels such as the GABAA receptor, glycine receptor and the nicotinic acetylcholine receptor have also been shown to mediate synaptic excitation and inhibition. Many anti-epileptic drugs (AED) used clinically act on these voltage-gated or ligand-gated ion channels to modify the bursting properties of neurons. However, it remains unclear how neural ensembles are synchronized and how abnormal discharge of neurons are propagated. Extracellular signaling molecules, including brain-derived neurotrophic factor (BDNF), thyrotropin-releasing hormone (TRH), corticotrophin releasing hormone (CRH) and neuropeptide Y (NPY), are upregulated as a result of seizure. These signaling molecules, in turn, may modulate neuronal membrane excitation and other neural plastic alterations important in epileptogenesis, such as gliosis, neuronal death and synaptic reorganization.
Accordingly, there exists a need to identify therapeutic agents useful in treating cerebrovascular disease and seizure disorders. The present invention satisfies this need, and provides related advantages as well.